Accumulating evidence indicates that the development of highly invasive skin tumors may require multiple mutations at different loci and that over-expression or repression of key regulatory genes can cooperate to influence the development of cancer. Solar ultraviolet B (UVB) induces the expression and activities of ornithine decarboxylase (ODC) and cyclooxygenase-2 (COX-2). ODC is the rate limiting enzyme for synthesis of polyamines, which are essential for the growth and differentiation of all cells. COX-2 expression leads to enhanced synthesis of prostaglandins (PGs), particularly PGE2 in the skin. We have developed genetically engineered murine models coupled with specific pharmacological approaches to show that both ODC and COX-2 over-expression in murine skin enhances the growth of non-melanoma skin cancers (NMSCs), and that down-regulation of ODC or COX-2 attenuates the growth of these tumors only partially. Human squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) both over- express ODC and COX-2. We and others have shown that their over-expression underlies the pathogenesis of NMSCs. SCCs show their high expression particularly at the interface where they invade normal tissue. However, in BCCs, which are locally invasive and metastasize only rarely, COX-2 expression occurs primarily in stromal cells, whereas ODC expression is also comparatively less prominent. In this project we will test the hypothesis that both pathways can cooperate in the pathogenesis of NMSCs and that their temporal and spatial regulation determines the tumor phenotype and progression to a malignant phenotype. Since both augmented COX-2-generated PGE2 and ODC-dependent polyamine overproduction lead to enhanced proliferation, migration and invasiveness of cells carrying mutations in known tumor suppressor genes including p53 and ptch that characterize NMSCs, the combined inhibition of these molecular targets could provide an entirely novel approach to the chemoprevention of this neoplasm. We also proposed to investigate the mechanism by which combined over expression of ODC and COX-2 can lead to the pathogenesis of an invasive tumor phenotype. It is anticipated that the information generated in these studies could be quickly translated into clinical trials employing the uniquely available high risk population at the University of Alabama Medical Center. PUBLIC HEALTH RELEVANCE: Both COX-2 and ODC are consistently up-regulated during pathogenesis of non- melanoma skin cancers (NMSCs). However, blocking either one of these molecular targets only partially blocks the development of NMSCs. This proposal attempts to block both of these molecular targets to abrogate the pathogenesis of the most common human cancer, NMSCs.